Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of cysts that compress and damage the surrounding normal renal parenchyma, which in turn leads to an eventual decline in renal function. Although two genes have been linked to the ADPKD phenotype, PKD1 and PKD2, majority of cases are due to mutations in the PKD1 gene, which encodes for polycystin-1 (PC1). In order to develop treatments for ADPKD patients, it is necessary to understand the signaling mechanisms associated with PC1 function. Therefore, the goal of this application is to explore the novel role of presenilin-2 (PSEN2) in the control of PC1 signaling. PSEN2 is the catalytic subunit of -secretase, a protease that cleaves PC1, leading to the release of its C-terminal tail (CTT). The resulting PC1 CTT cleavage fragments appear to act as signaling molecules that participate in maintaining cell homeostasis. Although aspects of the signaling pathways associated with cleavage of PC1 CTT have been elucidated, the stimuli that activate PSEN2-mediated PC1 CTT cleavage and the potential involvement of PSEN2 in cystogenesis remain unclear. We have previously determined that PSEN2 knockdown in HEK293 cells markedly reduces PC1 CTT cleavage. Our previous studies also suggest that PC1 CTT cleavage modulates the transcriptional activity of genes related to endoplasmic reticulum (ER) stress, and is induced by renal injuries associated with decreased flow. We hypothesize that PSEN2 is required for proper PC1 CTT cleavage and signaling, and that this function participates in preventing cystogenesis. We propose the following specific aims to support or refute our hypothesis: 1) Aim 1 will establish the concept that PSEN2-mediated PC1 CTT cleavage is stimulated by ER stress, a process that if perturbed has shown to lead to cyst formation. We will measure PC1 CTT cleavage using a luciferase-based assay in conditions of PSEN2 knockdown and ER stress, and identify the size of the particular fragment associated with this response; 2) Aim 2 will establish the concept that PSEN2-mediated cleavage of PC1 plays a critical role in the cyst-preventing activities of PC1, and that prevention of PC1 CTT enhances the capacity of renal injury to induce cyst formation. To do this, we will conduct phenotypic analyses on PSEN2-/- mice at baseline and in response to ischemia/reperfusion-induced acute renal injury. We expect that these molecular and physiological approaches may suggest new therapeutic targets for ADPKD treatment development. PUBLIC HEALTH RELEVANCE: Studies aimed at understanding the causes of cystic growth associated with autosomal polycystic kidney disease (ADPKD) have high public relevance since it is the leading genetic cause of renal disease, afflicting approximately 1 in every 1,000 individuals. It is currently known that mutations in PKD1, a gene that produces the polycystin-1 protein, causes cyst growth. Therefore, our studies will explore the regulatory mechanisms of this critical protein.